Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump

Autor:	Ward, David
Jazyk:	angličtina
Rok vydání:	2012
Předmět:	P-glycoprotein Pgp drug resistance cancer tumour MDR drug binding drug transport multidrug resistance chemotherapy
Druh dokumentu:	Diplomová práce
Popis:	P-glycoprotein (Pgp, ABCB1) is a polyspecific efflux transporter implicated in multidrug resistance in human cancers. In this study, tetramethylrhodamine-5-carbonyl azide (AzTMR) was covalently crosslinked to the Pgp drug binding pocket with a stoichiometry of 1. The Pgp-AzTMR adduct was functionally equivalent to unlabelled Pgp and retained its ability to transport Hoechst 33342. The binding site of AzTMR in Pgp was nonpolar, with a similar environment to that of propanol. Pgp-AzTMR could bind a second drug molecule, with a higher affinity for H-site drugs and lower affinity for other R-site drugs. Unlabelled Pgp interacted with dimeric versions of known Pgp modulators, binding them with higher affinity than the monomer. These compounds were also found to either stimulate or inhibit Pgp ATPase activity depending on the concentration. Pgp-AzTMR was able to bind dimeric drugs, indicating that 3 substrate moieties can fit into the binding pocket. The Canadian Cancer Society
Databáze:	Networked Digital Library of Theses & Dissertations
Externí odkaz:	http://hdl.handle.net/10214/3309 Zobrazit plný text záznamu